7. Project Summary/Abstract Funding is requested toward the purchase of a Thermo Scientific Q-Exactive High Field Mass Spectrometer (Q-Exactive HF MS) system which would provide a uniquely high performance mass spectrometer for the MS & Proteomics Resource within the Keck Laboratory at Yale University. The Q-Exactive HF is one of the newest benchtop quadrupole-Orbitrap MS platforms in its class with a leading edge ultra-high- field Orbitrap analyzer which enables scan speed up to 18 Hz, resolution up to 240,000, and sub-parts-per- million mass accuracy, as well as superior ion transmission and isolation characteristics with its Advanced Active Beam Guide (AABG) design. These advanced features make the new HF platform twice as fast and 5 to 10-fold more sensitive than its predecessor, the Q-Exactive Plus. Our demo of the requested QE-HF mass spectrometer show an improvement of up to 42% in number of peptides ID, and greater than 23% improvements in the number of proteins ID from a complex brain proteome source compared to QE-Plus. This will enable investigators to reach deeper into the human and other complex proteomes than is currently possible. The advances incorporated into the Q-Exactive HF also make it the ideal platform to support the LFQ and PTM technologies that have become highly requested services by the 300+ Yale and 200+ non-Yale users and investigators at 85 institutions who have utilized the MS & Proteomics Resource over the last two years. The demand for these technologies supported by Q-Exactive Plus has increased so rapidly that there is a constant 3+ weeks backlog for data collection even though the instrument has been running at maximum capacity (>95% Accessible User Time, AUT). Addition of the requested Q-Exactive HF to this Resource would reduce this backlog, preventing unnecessary delays to biomedical research advancement, as well as ensure that the Resource has the capability to benefit even more investigators who would like to use the technologies for their biomedical research. This application is supported by 25 investigators and their collaborators encompassing more than 14 different disciplinary research fields at Yale and 4 other institutions including Mt. Sinai School of Medicine, Tufts University, University of Connecticut Health Center, and Medical University of South Carolina who propose to carry out >40 biomedical research projects with strong proteomics components that depend upon the requested instrumentation. The proposed Major users of the Q-Exactive HF MS include PI of four NIH and National Centers (i.e. VA-Yale National Center for PTSD, Yale/NIDA Neuroproteomics Center, Mount Sinai Conte Center on Epigenetic Mechanisms of Depression, and Yale Alzheimer's Disease Research Center). The strengths of this proposal are manifold and include continuing strong institutional support (e.g. providing >18% in cost sharing in this proposal to purchase the necessary liquid chromatography component); sustained balanced operational budget of the Resource; and the continued usage of and collaboration with the Resource by hundreds of NIH-funded investigators annually.